bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2022‒12‒18
forty-five papers selected by
Anna Vainshtein
Craft Science Inc.
  1. CPNE1 regulates myogenesis through the PERK-eIF2α pathway mediated by endoplasmic reticulum stress.
  2. Simultaneous loss of skeletal muscle myosin heavy chain IIx and IIb causes severe skeletal muscle hypoplasia in postnatal mice.
  3. HMGB1 Promotes In Vitro and In Vivo Skeletal Muscle Atrophy through an IL-18-Dependent Mechanism.
  4. Single nuclei profiling identifies cell specific markers of skeletal muscle aging, frailty, and senescence.
  5. PDGF-B secreted from skeletal muscle enhances myoblast proliferation and myotube maturation via activation of the PDGFR signaling cascade.
  6. Apol9a regulates myogenic differentiation via the ERK1/2 pathway in C2C12 cells.
  7. Targeting the DP2 receptor alleviates muscle atrophy and diet-induced obesity in mice through oxidative myofiber transition.
  8. The inflammatory response, a mixed blessing for muscle homeostasis and plasticity.
  9. Muscle metabolic stress determines cancer cachexia severity in mice.
  10. MicroRNAs as the Sentinels of Redox and Hypertrophic Signalling.
  11. Irisin ameliorates age-associated sarcopenia and metabolic dysfunction.
  12. Tenotomy-induced muscle atrophy is sex-specific and independent of NFκB.
  13. Extracellular matrix: Brick and mortar in the skeletal muscle stem cell niche.
  14. Opposite Regulation of Homer Signal at the NMJ Postsynaptic Micro Domain between Slow- and Fast-Twitch Muscles in an Experimentally Induced Autoimmune Myasthenia Gravis (EAMG) Mouse Model.
  15. Skeletal muscle transcriptome is affected by age in severely burned mice.
  16. Growth arrest and DNA damage-inducible alpha regulates muscle repair and fat infiltration through ATP synthase F1 subunit alpha.
  17. The Role of Skeletal Muscle Mitochondria in Colorectal Cancer Related Cachexia: Friends or Foes?
  18. Nonsense-mediated mRNA decay promote C2C12 cell proliferation by targeting PIK3R5.
  19. Chromatin state distribution of residue-specific histone acetylation in early myoblast differentiation.
  20. Zebrafish Models for Skeletal Muscle Senescence: Lessons from Cell Cultures and Rodent Models.
  21. Skeletal muscle metabolism and contraction performance regulation by teneurin C-terminal-associated peptide-1.
  22. Mini-dCas13X-mediated RNA editing restores dystrophin expression in a humanized mouse model of Duchenne muscular dystrophy.
  23. O-GlcNAcylation of SIRT1 Protects against Cold Stress-Induced Skeletal Muscle Damage via Amelioration of Mitochondrial Homeostasis.
  24. Decreased methylglyoxal-mediated protein glycation in the healthy aging mouse model of ectopic expression of UCP1 in skeletal muscle.
  25. p21 induces a senescence program and skeletal muscle dysfunction.
  26. Digoxigenin-labeled RNA probes for untranslated regions enable the isoform-specific gene expression analysis of myosin heavy chains in whole-mount in situ hybridization.
  27. Plasma proteome profiling of healthy subjects undergoing bed rest reveals unloading-dependent changes linked to muscle atrophy.
  28. Alignment of Skeletal Muscle Cells Facilitates Acetylcholine Receptor Clustering and Neuromuscular Junction Formation with Co-Cultured Human iPSC-Derived Motor Neurons.
  29. Golgi Complex form and Function: A Potential Hub Role Also in Skeletal Muscle Pathologies?
  30. Proteolytic ectodomain shedding of muscle-specific tyrosine kinase in myasthenia gravis.
  31. Infection and chronic disease activate a brain-muscle signaling axis that regulates muscle performance.
  32. Muscle PGC-1α modulates hepatic mitophagy regulation during aging.
  33. AMP-activated protein kinase inhibition in fibro-adipogenic progenitors impairs muscle regeneration and increases fibrosis.
  34. Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4.
  35. Immunoproteasome Inhibition Ameliorates Aged Dystrophic Mouse Muscle Environment.
  36. Aging reduces ABHD5 protein content in the adipose tissue of mice: The reversal effect of exercise.
  37. Age, sex, and frailty modify the expression of common reference genes in skeletal muscle from ageing mice.
  38. Inflammaging: Implications in Sarcopenia.
  39. Exercise and mitochondrial remodeling to prevent age-related neurodegeneration.
  40. CRISPR-mediated generation and characterization of a Gaa homozygous c.1935C>A (p.D645E) Pompe disease knock-in mouse model recapitulating human infantile onset-Pompe disease.
  41. Divergent remodeling of the skeletal muscle metabolome over 24 h between young, healthy men and older, metabolically compromised men.
  42. Early clinical and pre-clinical therapy development in Nemaline Myopathy.
  43. Muscle 4EBP1 activation modifies the structure and function of the neuromuscular junction in mice.
  44. Genome-Wide Association Study Identifies CDKN1A as a Novel Locus Associated with Muscle Fiber Composition.
  45. 2023 On-site Padua Days on Muscle and Mobiliy Medicine: Call for speakers.
  1. Cell Tissue Res. 2022 Dec 16.
    CPNE1 regulates myogenesis through the PERK-eIF2α pathway mediated by endoplasmic reticulum stress.
    Lin Chen, Ling Pan, Yuexi Zeng, Xiaonan Zhu, Li You.
      Sarcopenia is characterized by a progressive reduction in muscle mass or muscle physiological function associated with aging, but the relevant molecular mechanisms are not clear. Here, we identify the role of the myogenesis modifier CPNE1 in sarcopenia. CPNE1 is upregulated in aged skeletal muscles and young skeletal muscle satellite cells with palmitate-induced atrophy. The overexpression of CPNE1 hinders proliferation and differentiation and increases muscle atrophy characteristics in young skeletal muscle-derived satellite cells. In addition, CPNE1 overexpression disrupts the balance of mitochondrial fusion and division and causes endoplasmic reticulum stress. We found that the effects of CPNE1 on mitochondrial function are dependent on the PERK/eIF2α/ATF4 pathway. The overexpression of CPNE1 in young muscles alters membrane lipid composition, reduces skeletal muscle fibrosis regeneration, and exercise capacity in mice. These effects were reversed by PERK inhibitor GSK2606414. Moreover, immunoprecipitation indicates that CPNE1 overexpression greatly increased the acetylation of PERK. Therefore, CPNE1 is an important modifier that drives mitochondrial homeostasis to regulate myogenic cell proliferation and differentiation via the PERK-eIF2α pathway, which could be a valuable target for age-related sarcopenia.
    Keywords:  CPNE1; Endoplasmic reticulum stress; PERK; Sarcopenia; eIF2α
    DOI:  https://doi.org/10.1007/s00441-022-03720-y
  2. FASEB J. 2023 Jan;37(1): e22692
    Simultaneous loss of skeletal muscle myosin heavy chain IIx and IIb causes severe skeletal muscle hypoplasia in postnatal mice.
    Keisuke Hitachi, Yuri Kiyofuji, Hisateru Yamaguchi, Masashi Nakatani, Masafumi Inui, Kunihiro Tsuchida.
      The skeletal muscle myosin heavy chain (MyHC) is a fundamental component of the sarcomere structure and muscle contraction. Two of the three adult fast MyHCs, MyHC-IIx and MyHC-IIb, are encoded by Myh1 and Myh4, respectively. However, skeletal muscle disorders have not yet been linked to these genes in humans. MyHC-IIb is barely detectable in human skeletal muscles. Thus, to characterize the molecular function of skeletal muscle MyHCs in humans, investigation of the effect of simultaneous loss of MyHC-IIb and other MyHCs on skeletal muscle in mice is essential. Here, we generated double knockout (dKO) mice with simultaneous loss of adult fast MyHCs by introducing nonsense frameshift mutations into the Myh1 and Myh4 genes. The dKO mice appeared normal after birth and until 2 weeks of age but showed severe skeletal muscle hypoplasia after 2 weeks. In 3-week-old dKO mice, increased expression of other skeletal muscle MyHCs, such as MyHC-I, MyHC-IIa, MyHC-neo, and MyHC-emb, was observed. However, these expressions were not sufficient to compensate for the loss of MyHC-IIb and MyHC-IIx. Moreover, the aberrant sarcomere structure with altered expression of sarcomere components was observed in dKO mice. Our findings imply that the simultaneous loss of MyHC-IIb and MyHC-IIx is substantially detrimental to postnatal skeletal muscle function and will contribute to elucidating the molecular mechanisms of skeletal muscle wasting disorders caused by the loss of skeletal muscle MyHCs.
    Keywords:  genome editing; hypoplasia; muscle atrophy; myofiber; myosin heavy chain; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.202200581R
  3. Cells. 2022 Dec 06. pii: 3936. [Epub ahead of print]11(23):
    HMGB1 Promotes In Vitro and In Vivo Skeletal Muscle Atrophy through an IL-18-Dependent Mechanism.
    Trung-Loc Ho, Chih-Hsin Tang, Sunny Li-Yun Chang, Chun-Hao Tsai, Hsien-Te Chen, Chen-Ming Su.
      Skeletal muscle atrophy occurs due to muscle wasting or reductions in protein associated with aging, injury, and inflammatory processes. High-mobility group box-1 (HMGB1) protein is passively released from necrotic cells and actively secreted by inflammatory cells, and is implicated in the pathogenesis of various inflammatory and immune diseases. HMGB1 is upregulated in muscle inflammation, and circulating levels of the proinflammatory cytokine interleukin-18 (IL-18) are upregulated in patients with sarcopenia, a muscle-wasting disease. We examined whether an association exists between HMGB1 and IL-18 signaling in skeletal muscle atrophy. HMGB1-induced increases of IL-18 levels enhanced the expression of muscle atrophy markers and inhibited myogenic marker expression in C2C12 and G7 myoblast cell lines. HMGB1-induced increases of IL-18 production in C2C12 cells involved the RAGE/p85/Akt/mTOR/c-Jun signaling pathway. HMGB1 short hairpin RNA (shRNA) treatment rescued the expression of muscle-specific differentiation markers in murine C2C12 myotubes and in mice with glycerol-induced muscle atrophy. HMGB1 and IL-18 signaling was suppressed in the mice after HMGB1 shRNA treatment. These findings suggest that the HMGB1/IL-18 axis is worth targeting for the treatment of skeletal muscle atrophy.
    Keywords:  HMGB1; IL-18; inflammation; myogenesis; skeletal muscle atrophy
    DOI:  https://doi.org/10.3390/cells11233936
  4. Aging (Albany NY). 2022 Dec 13. 14
    Single nuclei profiling identifies cell specific markers of skeletal muscle aging, frailty, and senescence.
    Kevin Perez, Serban Ciotlos, Julia McGirr, Chandani Limbad, Ryosuke Doi, Joshua P Nederveen, Mats I Nilsson, Daniel A Winer, William Evans, Mark Tarnopolsky, Judith Campisi, Simon Melov.
      Aging is accompanied by a loss of muscle mass and function, termed sarcopenia, which causes numerous morbidities and economic burdens in human populations. Mechanisms implicated in age-related sarcopenia or frailty include inflammation, muscle stem cell depletion, mitochondrial dysfunction, and loss of motor neurons, but whether there are key drivers of sarcopenia are not yet known. To gain deeper insights into age-related muscle loss, we performed transcriptome profiling on lower limb muscle biopsies from 72 young, elderly, and frail human subjects using bulk RNA-seq (N = 72) and single-nuclei RNA-seq (N = 17). This combined approach revealed changes in gene expression that occur with age and frailty in multiple cell types comprising mature skeletal muscle. Notably, we found increased expression of the genes MYH8 and PDK4, and decreased expression of the gene IGFN1, in aged muscle. We validated several key genes changes in fixed human muscle tissue using digital spatial profiling. We also identified a small population of nuclei that express CDKN1A, present only in aged samples, consistent with p21cip1-driven senescence in this subpopulation. Overall, our findings identify unique cellular subpopulations in aged and sarcopenic skeletal muscle, which will facilitate the development of new therapeutic strategies to combat age-related frailty.
    Keywords:  aging; muscle; sarcopenia; senescence; transcriptomics
    DOI:  https://doi.org/10.18632/aging.204435
  5. Biochem Biophys Res Commun. 2022 Nov 28. pii: S0006-291X(22)01642-4. [Epub ahead of print]639 169-175
    PDGF-B secreted from skeletal muscle enhances myoblast proliferation and myotube maturation via activation of the PDGFR signaling cascade.
    Hiroki Hamaguchi, Kitora Dohi, Takaomi Sakai, Masato Taoka, Toshiaki Isobe, Tsubasa S Matsui, Shinji Deguchi, Yasuro Furuichi, Nobuharu L Fujii, Yasuko Manabe.
      Myokines, secreted factors from skeletal muscle, act locally on muscle cells or satellite cells, which is important in regulating muscle mass and function. Here, we found platelet-derived growth factor subunit B (PDGF-B) is constitutively secreted from muscle cells without muscle contraction. Furthermore, PDGF-B secretion increased with myoblast to myotube differentiation. To examine the role of PDGF-B as a paracrine or autocrine myokine, myoblasts or myotubes were treated with PDGF-B. As a result, myoblast proliferation was significantly enhanced via several signaling pathways. Intriguingly, myotubes treated with PDGF-B showed enhanced maturation as indicated by their increased myotube diameter, myosin heavy chain expression, and strengthened contractile force. These findings suggest that PDGF-B is constitutively secreted by myokines to enhance myoblast proliferation and myotube maturation, which may contribute to skeletal muscle regeneration.
    Keywords:  Muscle hypertrophy; Muscle regeneration; Myoblast; Myokine; Myotube; PDGF-B
    DOI:  https://doi.org/10.1016/j.bbrc.2022.11.085
  6. Front Pharmacol. 2022 ;13 942061
    Apol9a regulates myogenic differentiation via the ERK1/2 pathway in C2C12 cells.
    Xuan Jiang, Siyu Ji, Siyuan Cui, Rong Wang, Wei Wang, Yongquan Chen, Shenglong Zhu.
      Background: The rising prevalence of obesity and its complications is a big challenge for the global public health. Obesity is accompanied by biological dysfunction of skeletal muscle and the development of muscle atrophy. The deep knowledge of key molecular mechanisms underlying myogenic differentiation is crucial for discovering novel targets for the treatment of obesity and obesity-related muscle atrophy. However, no effective target is currently known for obesity-induced skeletal muscle atrophy. Methods: Transcriptomic analyses were performed to identify genes associated with the regulation of myogenic differentiation and their potential mechanisms of action. C2C12 cells were used to assess the myogenic effect of Apol9a through immunocytochemistry, western blotting, quantitative polymerase chain reaction, RNA interference or overexpression, and lipidomics. Results: RNA-seq of differentiated and undifferentiated C2C12 cells revealed that Apol9a expression significantly increased following myogenic differentiation and decreased during obesity-induced muscle atrophy. Apol9a silencing in these C2C12 cells suppressed the expression of myogenesis-related genes and reduced the accumulation of intracellular triglycerides. Furthermore, RNA-seq and western blot results suggest that Apol9a regulates myogenic differentiation through the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). This assumption was subsequently confirmed by intervention with PD98059. Conclusion: In this study, we found that Apol9a regulates myogenic differentiation via the ERK1/2 pathway. These results broaden the putative function of Apol9a during myogenic differentiation and provide a promising therapeutic target for intervention in obesity and obesity-induced muscle atrophy.
    Keywords:  Apol9a; C2C12; ERK1/2; myogenesis; obesity
    DOI:  https://doi.org/10.3389/fphar.2022.942061
  7. J Cachexia Sarcopenia Muscle. 2022 Dec 16.
    Targeting the DP2 receptor alleviates muscle atrophy and diet-induced obesity in mice through oxidative myofiber transition.
    Huying Ning, Huiwen Ren, Yan Zhao, HaiFang Yin, Zhenji Gan, Yujun Shen, Ying Yu.
      BACKGROUND: Mammalian skeletal muscles consist of two main fibre types: slow-twitch (type I, oxidative) and fast-twitch (type IIa, fast oxidative; type IIb/IIx, fast glycolytic). Muscle fibre composition switch is closely associated with chronic diseases such as muscle atrophy, obesity, type II diabetes and athletic performance. Prostaglandin D2 (PGD2 ) is a bioactive lipid derived from arachidonic acid that aggravates muscle damage and wasting during muscle atrophy. This study aimed to investigate the precise mechanisms underlying PGD2 -mediated muscle homeostasis and myogenesis.METHODS: Skeletal muscle-specific PGD2 receptor DP2-deficient mice (DP2fl/fl HSACre ) and their littermate controls (DP2fl/fl ) were subjected to exhaustive exercise and fed a high-fat diet (HFD). X-linked muscular dystrophy (MDX) mice and HFD-challenged mice were treated with the selective DP2 inhibitor CAY10471. Exercise tolerance, body weight, glycometabolism and skeletal muscle fibre composition were measured to determine the role of the skeletal muscle PGD2 /DP2 signalling axis in obesity and muscle disorders. Multiple genetic and pharmacological approaches were also used to investigate the intracellular signalling cascades underlying the PGD2 /DP2-mediated skeletal muscle fibre transition.
    RESULTS: PGD2 generation and DP2 expression were significantly upregulated in the hindlimb muscles of HFD-fed mice (P < 0.05 or P < 0.01 vs. normal chow diet). Compared with DP2fl/fl mice, DP2fl/fl HSACre mice exhibited remarkable glycolytic-to-oxidative fibre-type transition in hindlimb muscles and were fatigue resistant during endurance exercise (154.9 ± 6.0 vs. 124.2 ± 8.1 min, P < 0.05). DP2fl/fl HSACre mice fed an HFD showed less weight gain (P < 0.05) and hepatic lipid accumulation (P < 0.01), reduced insulin resistance and enhanced energy expenditure (P < 0.05) compared with DP2fl/fl mice. Mechanistically, DP2 deletion promoted the nuclear translocation of nuclear factor of activated T cells 1 (NFATc1) by suppressing RhoA/Rho-associated kinase 2 (ROCK2) signalling, which led to enhanced oxidative fibre-specific gene transcription in muscle cells. Treatment with CAY10471 enhanced NFATc1 activity in the skeletal muscles and ameliorated HFD-induced obesity (P < 0.05 vs. saline) and insulin resistance in mice. CAY10471 also enhanced exercise tolerance in MDX mice (100.8 ± 8.0 vs. 68.9 ± 11.1 min, P < 0.05 vs. saline) by increasing the oxidative fibre-type ratio in the muscles (45.1 ± 2.3% vs. 32.3 ± 2.6%, P < 0.05 vs. saline).
    CONCLUSIONS: DP2 activation suppresses oxidative fibre transition via RhoA/ROCK2/NFATc1 signalling. The inhibition of DP2 may be a potential therapeutic approach against obesity and muscle disorders.
    Keywords:  DP2 receptor; NFATc1; muscle fibre; oxidative; prostaglandin D2
    DOI:  https://doi.org/10.1002/jcsm.13136
  8. Front Physiol. 2022 ;13 1032450
    The inflammatory response, a mixed blessing for muscle homeostasis and plasticity.
    Zineb Bouredji, Anteneh Argaw, Jérôme Frenette.
      Skeletal muscle makes up almost half the body weight of heathy individuals and is involved in several vital functions, including breathing, thermogenesis, metabolism, and locomotion. Skeletal muscle exhibits enormous plasticity with its capacity to adapt to stimuli such as changes in mechanical loading, nutritional interventions, or environmental factors (oxidative stress, inflammation, and endocrine changes). Satellite cells and timely recruited inflammatory cells are key actors in muscle homeostasis, injury, and repair processes. Conversely, uncontrolled recruitment of inflammatory cells or chronic inflammatory processes leads to muscle atrophy, fibrosis and, ultimately, impairment of muscle function. Muscle atrophy and loss of function are reported to occur either in physiological situations such as aging, cast immobilization, and prolonged bed rest, as well as in many pathological situations, including cancers, muscular dystrophies, and several other chronic illnesses. In this review, we highlight recent discoveries with respect to the molecular mechanisms leading to muscle atrophy caused by modified mechanical loading, aging, and diseases. We also summarize current perspectives suggesting that the inflammatory process in muscle homeostasis and repair is a double-edged sword. Lastly, we review recent therapeutic approaches for treating muscle wasting disorders, with a focus on the RANK/RANKL/OPG pathway and its involvement in muscle inflammation, protection and regeneration processes.
    Keywords:  cachexia; inflammation; muscle atrophy; muscle-bone crosstalk; sarcopenia
    DOI:  https://doi.org/10.3389/fphys.2022.1032450
  9. Front Physiol. 2022 ;13 1033932
    Muscle metabolic stress determines cancer cachexia severity in mice.
    Christiano Alves, Laurie Goodyear, Patricia Brum.
      Objectives: To determine the metabolic effects of cancer-conditioned media on myotube metabolism and to understand whether the variability of these effects is associated with cancer cachexia progression. Materials and methods: We established single-cell clones from murine Lewis lung carcinoma (LLC) cells and generated conditioned media from each clonal line. Differentiated primary mouse myotubes were incubated with conditioned media derived from each individual clonal cell line. After initial analysis, we selected a specific LLC clonal cell line that failed to induce metabolic stress in myotubes for further investigation in vitro and in vivo. Results: Short-term incubation with conditioned media from 10/34 LLC clonal cells failed to affect oxygen consumption rate (OCR) in myotubes. Incubation with parental LLC-conditioned media decreased protein content and changed the expression of key regulators of muscle function in myotubes, but the incubation of conditioned media from a selected clone that failed to affect OCR in myotubes also did not affect protein content and expression of muscle regulators. Mice injected with parental LLC cells had a significantly reduced body mass and muscle wasting compared to the mice injected with cells derived from this selected LLC clone. Conclusion: Factors secreted by LLC cells induce metabolic stress in primary myotubes and induce cancer cachexia in mice. However, a selected clonal LLC cell line that failed to induce metabolic stress in myotubes also promoted weaker catabolism in mice. These novel findings establish that early disruption of muscle oxidative metabolism is associated with cancer cachexia progression.
    Keywords:  atrophy; lung carcinoma; muscle wasting; oxidative metabolism; oxidative stress
    DOI:  https://doi.org/10.3389/fphys.2022.1033932
  10. Int J Mol Sci. 2022 Nov 25. pii: 14716. [Epub ahead of print]23(23):
    MicroRNAs as the Sentinels of Redox and Hypertrophic Signalling.
    Filip Kolodziej, Brian McDonagh, Nicole Burns, Katarzyna Goljanek-Whysall.
      Oxidative stress and inflammation are associated with skeletal muscle function decline with ageing or disease or inadequate exercise and/or poor diet. Paradoxically, reactive oxygen species and inflammatory cytokines are key for mounting the muscular and systemic adaptive responses to endurance and resistance exercise. Both ageing and lifestyle-related metabolic dysfunction are strongly linked to exercise redox and hypertrophic insensitivity. The adaptive inability and consequent exercise intolerance may discourage people from physical training resulting in a vicious cycle of under-exercising, energy surplus, chronic mitochondrial stress, accelerated functional decline and increased susceptibility to serious diseases. Skeletal muscles are malleable and dynamic organs, rewiring their metabolism depending on the metabolic or mechanical stress resulting in a specific phenotype. Endogenous RNA silencing molecules, microRNAs, are regulators of these metabolic/phenotypic shifts in skeletal muscles. Skeletal muscle microRNA profiles at baseline and in response to exercise have been observed to differ between adult and older people, as well as trained vs. sedentary individuals. Likewise, the circulating microRNA blueprint varies based on age and training status. Therefore, microRNAs emerge as key regulators of metabolic health/capacity and hormetic adaptability. In this narrative review, we summarise the literature exploring the links between microRNAs and skeletal muscle, as well as systemic adaptation to exercise. We expand a mathematical model of microRNA burst during adaptation to exercise through supporting data from the literature. We describe a potential link between the microRNA-dependent regulation of redox-signalling sensitivity and the ability to mount a hypertrophic response to exercise or nutritional cues. We propose a hypothetical model of endurance exercise-induced microRNA "memory cloud" responsible for establishing a landscape conducive to aerobic as well as anabolic adaptation. We suggest that regular aerobic exercise, complimented by a healthy diet, in addition to promoting mitochondrial health and hypertrophic/insulin sensitivity, may also suppress the glycolytic phenotype and mTOR signalling through miRNAs which in turn promote systemic metabolic health.
    Keywords:  ageing; microRNAs; muscle; redox; sarcopenia
    DOI:  https://doi.org/10.3390/ijms232314716
  11. J Cachexia Sarcopenia Muscle. 2022 Dec 12.
    Irisin ameliorates age-associated sarcopenia and metabolic dysfunction.
    Mingwei Guo, Jing Yao, Jin Li, Jun Zhang, Dongmei Wang, Hui Zuo, Yi Zhang, Bo Xu, Yinzhao Zhong, Fei Shen, Jian Lu, Shuzhe Ding, Cheng Hu, Lingyan Xu, Junjie Xiao, Xinran Ma.
      BACKGROUND: Age-associated sarcopenia is characterized of progressed loss of skeletal muscle power, mass, and function, which affects human physical activity and life quality. Besides, accompanied with sarcopenia, aged population also faces a series of metabolic dysfunctions. Irisin, the cleaved form of fibronectin type III domain-containing protein 5 (FNDC5), is a myokine induced by exercise and has been shown to exert multiple beneficial effects on health. The goal of the study is to investigate the alterations of Fndc5/irisin in skeletal muscles during ageing and whether irisin administration could ameliorate age-associated sarcopenia and metabolic dysfunction.METHODS: The mRNA and protein levels of FNDC5/irisin in skeletal muscle and serum from 2- and 24-month-old mice or human subjects were analysed using qRT-PCR and western blot. FNDC5/irisin knockout mice were generated to investigate the consequences of FNDC5/irisin deletion on skeletal muscle mass, as well as morphological and molecular changes in muscle during ageing via histological and molecular analysis. To identify the therapeutic effects of chronic irisin treatment in mice during ageing, in vivo intraperitoneal administration of 2 mg/kg recombinant irisin was performed three times per week in ageing mice (14-month-old) for 4 months or in aged mice (22-month-old) for 1 month to systematically investigate irisin's effects on age-associated sarcopenia and metabolic performances, including grip strength, body weights, body composition, insulin sensitivity, energy expenditure, serum parameters and phenotypical and molecular changes in fat and liver.
    RESULTS: We showed that the expression levels of irisin, as well as its precursor Fndc5, were reduced at mRNA and protein expression levels in muscle during ageing. In addition, via phenotypic analysis of FNDC5/irisin knockout mice, we found that FNDC5/irisin deficiency in aged mice exhibited aggravated muscle atrophy including smaller grip strength (-3.23%, P < 0.05), muscle weights (quadriceps femoris [QU]: -20.05%; gastrocnemius [GAS]: -17.91%; tibialis anterior [TA]: -19.51%, all P < 0.05), fibre size (QU: P < 0.01) and worse molecular phenotypes compared with wild-type mice. We then delivered recombinant irisin protein intraperitoneally into ageing or aged mice and found that it could improve sarcopenia with grip strength (+18.42%, P < 0.01 or +13.88%, P < 0.01), muscle weights (QU: +9.02%, P < 0.01 or +16.39%, P < 0.05), fibre size (QU: both P < 0.05) and molecular phenotypes and alleviated age-associated fat tissues expansion, insulin resistance and hepatic steatosis (all P < 0.05), accompanied with altered gene signatures.
    CONCLUSIONS: Together, this study revealed the importance of irisin in the maintenance of muscle physiology and systematic energy homeostasis during ageing and suggested a potent therapeutic strategy against age-associated metabolic diseases via irisin administration.
    Keywords:  FNDC5; ageing; irisin; metabolic dysfunction; sarcopenia
    DOI:  https://doi.org/10.1002/jcsm.13141
  12. Elife. 2022 Dec 12. pii: e82016. [Epub ahead of print]11
    Tenotomy-induced muscle atrophy is sex-specific and independent of NFκB.
    Gretchen A Meyer, Stavros Thomopoulos, Yousef Abu-Amer, Karen C Shen.
      The nuclear factor-κB (NFκB) pathway is a major thoroughfare for skeletal muscle atrophy and is driven by diverse stimuli. Targeted inhibition of NFκB through its canonical mediator IKKβ effectively mitigates loss of muscle mass across many conditions, from denervation to unloading to cancer. In this study, we used gain- and loss-of-function mouse models to examine the role of NFκB in muscle atrophy following rotator cuff tenotomy - a model of chronic rotator cuff tear. IKKβ was knocked down or constitutively activated in muscle-specific inducible transgenic mice to elicit a 2-fold gain or loss of NFκB signaling. Surprisingly, neither knockdown of IKKβ nor overexpression of caIKKβ significantly altered the loss of muscle mass following tenotomy. This finding was consistent across measures of morphological adaptation (fiber cross-sectional area, fiber length, fiber number), tissue pathology (fibrosis and fatty infiltration) and intracellular signaling (ubiquitin-proteasome, autophagy). Intriguingly, late-stage tenotomy-induced atrophy was exacerbated in male mice compared to female mice. This sex specificity was driven by ongoing decreases in fiber cross-sectional area, which paralleled the accumulation of large autophagic vesicles in male, but not female muscle. These findings suggest that tenotomy-induced atrophy is not dependent on NFκB and instead may be regulated by autophagy in a sex-specific manner.
    Keywords:  medicine; mouse
    DOI:  https://doi.org/10.7554/eLife.82016
  13. Front Cell Dev Biol. 2022 ;10 1056523
    Extracellular matrix: Brick and mortar in the skeletal muscle stem cell niche.
    Svenja C Schüler, Yuguo Liu, Simon Dumontier, Michel Grandbois, Emmeran Le Moal, Ddw Cornelison, C Florian Bentzinger.
      The extracellular matrix (ECM) is an interconnected macromolecular scaffold occupying the space between cells. Amongst other functions, the ECM provides structural support to tissues and serves as a microenvironmental niche that conveys regulatory signals to cells. Cell-matrix adhesions, which link the ECM to the cytoskeleton, are dynamic multi-protein complexes containing surface receptors and intracellular effectors that control various downstream pathways. In skeletal muscle, the most abundant tissue of the body, each individual muscle fiber and its associated muscle stem cells (MuSCs) are surrounded by a layer of ECM referred to as the basal lamina. The core scaffold of the basal lamina consists of self-assembling polymeric laminins and a network of collagens that tether proteoglycans, which provide lateral crosslinking, establish collateral associations with cell surface receptors, and serve as a sink and reservoir for growth factors. Skeletal muscle also contains the fibrillar collagenous interstitial ECM that plays an important role in determining tissue elasticity, connects the basal laminae to each other, and contains matrix secreting mesenchymal fibroblast-like cell types and blood vessels. During skeletal muscle regeneration fibroblast-like cell populations expand and contribute to the transitional fibronectin-rich regenerative matrix that instructs angiogenesis and MuSC function. Here, we provide a comprehensive overview of the role of the skeletal muscle ECM in health and disease and outline its role in orchestrating tissue regeneration and MuSC function.
    Keywords:  MuSCs; extracellular matrix; muscle stem cells; satellite cells; skeletal muscle; stem cell niche
    DOI:  https://doi.org/10.3389/fcell.2022.1056523
  14. Int J Mol Sci. 2022 Nov 30. pii: 15052. [Epub ahead of print]23(23):
    Opposite Regulation of Homer Signal at the NMJ Postsynaptic Micro Domain between Slow- and Fast-Twitch Muscles in an Experimentally Induced Autoimmune Myasthenia Gravis (EAMG) Mouse Model.
    Martin Schubert, Andreas Pelz, Gabor Trautmann, Katharina Block, Sandra Furlan, Martina Gutsmann, Siegfried Kohler, Pompeo Volpe, Dieter Blottner, Andreas Meisel, Michele Salanova.
      Accelerated postsynaptic remodelling and disturbance of neuromuscular transmission are common features of autoimmune neurodegenerative diseases. Homer protein isoform expression, crosslinking activity and neuromuscular subcellular localisation are studied in mouse hind limb muscles of an experimentally induced autoimmune model of Myasthenia Gravis (EAMG) and correlated to motor end plate integrity. Soleus (SOL), extensor digitorum longus (EDL) and gastrocnemius (GAS) skeletal muscles are investigated. nAChR membrane clusters were studied to monitor neuromuscular junction (NMJ) integrity. Fibre-type cross-sectional area (CSA) analysis is carried out in order to determine the extent of muscle atrophy. Our findings clearly showed that crosslinking activity of Homer long forms (Homer 1b/c and Homer2a/b) are decreased in slow-twitch and increased in fast-twitch muscle of EAMG whereas the short form of Homer that disrupts Homer crosslinking (Homer1a) is upregulated in slow-twitch muscle only. Densitometry analysis showed a 125% increase in Homer protein expression in EDL, and a 45% decrease in SOL of EAMG mice. In contrast, nAChR fluorescence pixel intensity decreased in endplates of EAMG mice, more distinct in type-I dominant SOL muscle. Morphometric CSA of EAMG vs. control (CTR) revealed a significant reduction in EDL but not in GAS and SOL. Taken together, these results indicate that postsynaptic Homer signalling is impaired in slow-twitch SOL muscle from EAMG mice and provide compelling evidence suggesting a functional coupling between Homer and nAChR, underscoring the key role of Homer in skeletal muscle neurophysiology.
    Keywords:  Homer isoform expression; Myasthenia Gravis; NMJ adaptation; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms232315052
  15. Sci Rep. 2022 Dec 14. 12(1): 21584
    Skeletal muscle transcriptome is affected by age in severely burned mice.
    Juquan Song, Steven G Widen, Steven E Wolf, Amina Ei Ayadi.
      Severe burn results in muscle wasting affecting quality of life in both children and adults. Biologic metabolic profiles are noticeably distinctive in childhood. We posit that muscle gene expression profiles are differentially regulated in response to severe burns in young animals. Twelve C57BL6 male mice, including young (5 weeks-old) and adults (11 weeks-old), received either scald burn, or sham procedure. Mouse muscle tissue was harvested 24 h later for Next Generation Sequence analysis. Our results showed 662 downregulated and 450 upregulated genes in gastrocnemius of young mice compared to adults without injury. After injury, we found 74/75 downregulated genes and 107/128 upregulated genes in both burned groups compared to respective uninjured age groups. VEGFA-VEGFR2, focal adhesion, and nuclear receptor meta-pathways were the top 3 gene pathways undergoing a differential change in response to age. Of note, the proteasome degradation pathway showed the most similar changes in both adult and young burned animals. This study demonstrates the characteristic profile of gene expression in skeletal muscle in young and adult burned mice. Prominent age effects were revealed in transcriptional levels with increased alterations of genes, miRNAs, pathways, and interactions.
    DOI:  https://doi.org/10.1038/s41598-022-26040-1
  16. J Cachexia Sarcopenia Muscle. 2022 Dec 13.
    Growth arrest and DNA damage-inducible alpha regulates muscle repair and fat infiltration through ATP synthase F1 subunit alpha.
    Wenjing You, Shiqi Liu, Jianfei Ji, Defeng Ling, Yuang Tu, Yanbing Zhou, Wentao Chen, Teresa G Valencak, Yizhen Wang, Tizhong Shan.
      BACKGROUND: Skeletal muscle fat infiltration is a common feature during ageing, obesity and several myopathies associated with muscular dysfunction and sarcopenia. However, the regulatory mechanisms of intramuscular adipogenesis and strategies to reduce fat infiltration in muscle remain unclear. Here, we identified the growth arrest and DNA damage-inducible alpha (GADD45A), a stress-inducible histone folding protein, as a critical regulator of intramuscular fat (IMAT) infiltration.METHODS: To explore the role of GADD45A on IMAT infiltration and muscle regeneration, the gain or loss function of GADD45A in intramuscular preadipocytes was performed. The adipocyte-specific GADD45A knock-in (KI) mice and high IMAT-infiltrated muscle model by glycerol injection (50 μL of 50% v/v GLY) were generated. RNA-sequencing, histological changes, gene expression, lipid metabolism, mitochondrial function and the effect of dietary factor epigallocatechin-3-gallate (EGCG) treatment (100 mg/kg) on IMAT infiltration were studied.
    RESULTS: The unbiased transcriptomics data analysis indicated that GADD45A expression positively correlates with IMAT infiltration and muscle metabolic disorders in humans (correlation: young vs. aged people, Gadd45a and Cebpa, r2  = 0.20, P < 0.05) and animals (correlation: wild-type [WT] vs. mdx mice, Gadd45a and Cebpa, r2  = 0.38, P < 0.05; NaCl vs. GLY mice, Gadd45a and Adipoq/Fabp4, r2  = 0.80/0.71, both P < 0.0001). In vitro, GADD45A overexpression promotes intramuscular preadipocyte adipogenesis, upregulating the expression of adipogenic genes (Ppara: +47%, Adipoq: +28%, P < 0.001; Cebpa: +135%, Fabp4: +16%, P < 0.01; Pparg: +66%, Leptin: +77%, P < 0.05). GADD45A knockdown robustly decreased lipid accumulation (Pparg: -57%, Adipoq: -35%, P < 0.001; Fabp4: -37%, P < 0.01; Leptin: -28%, P < 0.05). GADD45A KI mice exhibit inhibited skeletal muscle regeneration (myofibres: -40%, P < 0.01) and enhanced IMAT infiltration (adipocytes: +20%, P < 0.05). These KI mice have impaired exercise endurance and mitochondrial function. Mechanistically, GADD45A affects ATP synthase F1 subunit alpha (ATP5A1) ubiquitination degradation (ubiquitinated ATP5A1, P < 0.001) by recruiting the E3 ubiquitin ligase TRIM25, which decreases ATP synthesis (ATP production: -23%, P < 0.01) and inactivates the cAMP/PKA/LKB1 signalling pathway (cAMP: -36%, P < 0.01; decreased phospho-PKA and phospho-LKB1 protein content, P < 0.01). The dietary factor EGCG can protect against muscle fat infiltration (triglyceride: -64%, P < 0.05) via downregulating GADD45A (decreased GADD45A protein content, P < 0.001).
    CONCLUSIONS: Our findings reveal a crucial role of GADD45A in regulating muscle repair and fat infiltration and suggest that inhibition of GADD45A by EGCG might be a potential strategy to combat fat infiltration and its associated muscle dysfunction.
    Keywords:  EGCG; GADD45A; fat infiltration; intramuscular adipogenesis; metabolic disorder; skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.13134
  17. Int J Mol Sci. 2022 Nov 27. pii: 14833. [Epub ahead of print]23(23):
    The Role of Skeletal Muscle Mitochondria in Colorectal Cancer Related Cachexia: Friends or Foes?
    Britt van de Haterd, Kenneth Verboven, Frank Vandenabeele, Anouk Agten.
      Up to 60% of colorectal cancer (CRC) patients develop cachexia. The presence of CRC related cachexia is associated with more adverse events during systemic therapy, leading to a high mortality rate. The main manifestation in CRC related cachexia is the loss of skeletal muscle mass, resulting from an imbalance between skeletal muscle protein synthesis and protein degradation. In CRC related cachexia, systemic inflammation, oxidative stress, and proteolytic systems lead to mitochondrial dysfunction, resulting in an imbalanced skeletal muscle metabolism. Mitochondria fulfill an important function in muscle maintenance. Thus, preservation of the skeletal muscle mitochondrial homeostasis may contribute to prevent the loss of muscle mass. However, it remains elusive whether mitochondria play a benign or malignant role in the development of cancer cachexia. This review summarizes current (mostly preclinical) evidence about the role of skeletal muscle mitochondria in the development of CRC related cachexia. Future human research is necessary to determine the physiological role of skeletal muscle mitochondria in the development of human CRC related cachexia.
    Keywords:  cachexia; colorectal cancer; inflammation; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms232314833
  18. J Muscle Res Cell Motil. 2022 Dec 13.
    Nonsense-mediated mRNA decay promote C2C12 cell proliferation by targeting PIK3R5.
    Zhenzhou Huang, Yishu Peng, Yuhui Wei, Yanjie Tan.
      Nonsense mediated mRNA decay (NMD) is a highly conserved RNA quality control system, which can specifically clear abnormal mRNA and play an important role in tumorigenesis. Myoblast proliferation plays an important role in the repair of skeletal muscle injury and the development of myosarcoma, and is controlled by a variety of transcription factors and signals. The molecular mechanism by which NMD regulates the proliferation of myoblast cells is not completely clear. In this study, we found that the NMD activity of skeletal muscle is high in 1-week-old mice but decreases gradually with age, corresponding to a weakening capacity for muscle growth and regeneration. Here, we provide evidence that NMD plays an important role in myoblast proliferation and apoptosis. In addition, we found that PIK3R5 is an NMD substrate gene which can inhibit AKT activity and C2C12 cell proliferation. Therefore, NMD can target PIK3R5 to enhance AKT activity, which in turn promotes C2C12 cell proliferation. This study provides new insights into NMD regulatory mechanisms in muscular development and into potential novel therapeutic strategies for muscle atrophy.
    Keywords:  AKT activity; Myoblast proliferation; Nonsense-mediated mRNA decay; PIK3R5
    DOI:  https://doi.org/10.1007/s10974-022-09639-9
  19. J Big Data. 2022 ;9(1): 116
    Chromatin state distribution of residue-specific histone acetylation in early myoblast differentiation.
    Yuan Li, Saadia Khilji, Yan Z Mach, Jihong Chen, Qiao Li.
      Dynamic changes in epigenetic landscape reflect a critical command of lineage-specific gene expression. In an effort to discern the epigenetic regulatory networks of myogenic differentiation, we have used systematic and integrative approaches to explore multi-omics datasets on global myogenic gene expression, histone acetylation and acetyltransferase occupancy in view of distinct chromatin states. In this brief report, we discuss experimental design and provide a comprehensive assessment regarding data quality control, filtering and processing. We also define a gene-level overlap between RNA-seq and ChIP-seq datasets through integrative analyses to offer strategies for future use of the data. Furthermore, our analyses generate a blueprint on chromatin state distribution of residue-specific histone acetylation and concomitant association with histone acetyltransferase p300 in committed skeletal myoblasts and differential histone acetylation signatures at the onset of myoblast differentiation. These datasets can be further utilized to delineate the function of muscle-specific regulatory elements governed by other muscle myogenic regulators or signaling molecules.
    Keywords:  Epigenetics; Gene regulation; Histone acetylation; Histone acetyltransferase; Myogenesis; Stem cell differentiation
    DOI:  https://doi.org/10.1186/s40537-022-00667-3
  20. Molecules. 2022 Dec 06. pii: 8625. [Epub ahead of print]27(23):
    Zebrafish Models for Skeletal Muscle Senescence: Lessons from Cell Cultures and Rodent Models.
    Shogo Ichii, Izumi Matsuoka, Fumiyoshi Okazaki, Yasuhito Shimada.
      Human life expectancy has markedly increased over the past hundred years. Consequently, the percentage of elderly people is increasing. Aging and sarcopenic changes in skeletal muscles not only reduce locomotor activities in elderly people but also increase the chance of trauma, such as bone fractures, and the incidence of other diseases, such as metabolic syndrome, due to reduced physical activity. Exercise therapy is currently the only treatment and prevention approach for skeletal muscle aging. In this review, we aimed to summarize the strategies for modeling skeletal muscle senescence in cell cultures and rodents and provide future perspectives based on zebrafish models. In cell cultures, in addition to myoblast proliferation and myotube differentiation, senescence induction into differentiated myotubes is also promising. In rodents, several models have been reported that reflect the skeletal muscle aging phenotype or parts of it, including the accelerated aging models. Although there are fewer models of skeletal muscle aging in zebrafish than in mice, various models have been reported in recent years with the development of CRISPR/Cas9 technology, and further advancements in the field using zebrafish models are expected in the future.
    Keywords:  animal models; drug screening; sarcopenia; skeletal muscle enlargement
    DOI:  https://doi.org/10.3390/molecules27238625
  21. Front Physiol. 2022 ;13 1031264
    Skeletal muscle metabolism and contraction performance regulation by teneurin C-terminal-associated peptide-1.
    David W Hogg, Andrea L Reid, Thomas L Dodsworth, Yani Chen, Ross M Reid, Mei Xu, Mia Husic, Peggy R Biga, Andrew Slee, Leslie T Buck, Dalia Barsyte-Lovejoy, Marius Locke, David A Lovejoy.
      Skeletal muscle regulation is responsible for voluntary muscular movement in vertebrates. The genes of two essential proteins, teneurins and latrophilins (LPHN), evolving in ancestors of multicellular animals form a ligand-receptor pair, and are now shown to be required for skeletal muscle function. Teneurins possess a bioactive peptide, termed the teneurin C-terminal associated peptide (TCAP) that interacts with the LPHNs to regulate skeletal muscle contractility strength and fatigue by an insulin-independent glucose importation mechanism in rats. CRISPR-based knockouts and siRNA-associated knockdowns of LPHN-1 and-3 in the C2C12 mouse skeletal cell line shows that TCAP stimulates an LPHN-dependent cytosolic Ca2+ signal transduction cascade to increase energy metabolism and enhance skeletal muscle function via increases in type-1 oxidative fiber formation and reduce the fatigue response. Thus, the teneurin/TCAP-LPHN system is presented as a novel mechanism that regulates the energy requirements and performance of skeletal muscle.
    Keywords:  ATP; CRISPR; calcium; energy; evolution; latrophilin; mitochondria; teneurin
    DOI:  https://doi.org/10.3389/fphys.2022.1031264
  22. J Clin Invest. 2022 Dec 13. pii: e162809. [Epub ahead of print]
    Mini-dCas13X-mediated RNA editing restores dystrophin expression in a humanized mouse model of Duchenne muscular dystrophy.
    Guoling Li, Ming Jin, Zhifang Li, Qingquan Xiao, Jiajia Lin, Dong Yang, Yuanhua Liu, Xing Wang, Long Xie, Wenqin Ying, Haoqiang Wang, Erwei Zuo, Linyu Shi, Ning Wang, Wanjin Chen, Chunlong Xu, Hui Yang.
      Approximately 10% of monogenic diseases are caused by nonsense point mutations that generate premature termination codons (PTCs), resulting in a truncated protein and nonsense-mediated decay of the mutant mRNAs. Here, we demonstrate a mini-dCas13X-mediated RNA adenine base editing (mxABE) strategy to treat nonsense mutation-related monogenic diseases via A-to-G editing in a genetically humanized mouse model of Duchenne muscular dystrophy (DMD). Initially, we identified a nonsense point mutation (c.4174C>T, p.Gln1392*) in the DMD gene of a patient and validated its pathogenicity in humanized mice. In this model, single adeno-associated virus (AAV)-packaged mxABE reached A-to-G editing rates up to 84% in vivo, which is at least 20-fold greater compared to rates reported in previous studies using other RNA-editing modalities. Furthermore, mxABE restored robust expression of dystrophin protein to over 50% of wild-type (WT) levels by enabling PTC read-through in multiple muscle tissues. Importantly, systemic delivery of mxABE by AAV also rescued dystrophin expression to averages of 37%, 6%, and 54% of WT levels in the diaphragm, tibialis anterior, and heart muscle, respectively, as well as rescued muscle function. Our data strongly suggest that mxABE-based strategies may be a viable new treatment modality for DMD and other monogenic diseases.
    Keywords:  Gene therapy; Monogenic diseases; Muscle; Therapeutics
    DOI:  https://doi.org/10.1172/JCI162809
  23. Int J Mol Sci. 2022 Nov 22. pii: 14520. [Epub ahead of print]23(23):
    O-GlcNAcylation of SIRT1 Protects against Cold Stress-Induced Skeletal Muscle Damage via Amelioration of Mitochondrial Homeostasis.
    Yu Cao, Meng Zhang, Ye Li, Jingjing Lu, Wanhui Zhou, Xiaoshuang Li, Hao Shi, Bin Xu, Shize Li.
      Cold stress disturbs cellular metabolic and energy homeostasis, which is one of the causes of stress-induced illnesses. O-GlcNAcylation is a nutrient-sensing pathway involved in a myriad of cellular processes. It plays a key role in metabolic homeostasis. Nevertheless, a specific sensing mechanism linking skeletal muscle to O-GlcNAcylation in cold stress is unknown. In this study, O-GlcNAcylation of SIRT1 was targeted to explore the mechanism of skeletal muscle adaptation to cold stress. Ogt mKO aggravated skeletal muscle fibrosis induced by cold stress. At the same time, Ogt gene deletion accelerated the homeostasis imbalance and oxidative stress of skeletal muscle mitochondria induced by cold stress. In vitro results showed that inhibition of SIRT1's O-GlcNAcylation accelerated mild hypothermia induced mitochondrial homeostasis in mouse myogenic cells (C2C12 cells). However, overexpression of SIRT1's O-GlcNAcylation improved the above phenomena. Thus, these results reveal a protective role of OGT-SIRT1 in skeletal muscle's adaptation to cold stress, and our findings will provide new avenues to combat stress-induced diseases.
    Keywords:  O-GlcNAcylation; SIRT1; cold stress; metabolic homeostasis imbalance; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms232314520
  24. Redox Biol. 2022 Dec 06. pii: S2213-2317(22)00346-9. [Epub ahead of print]59 102574
    Decreased methylglyoxal-mediated protein glycation in the healthy aging mouse model of ectopic expression of UCP1 in skeletal muscle.
    Jinit Masania, Patrick Wijten, Susanne Keipert, Mario Ost, Susanne Klaus, Naila Rabbani, Paul J Thornalley.
      Mice with ectopic expression of uncoupling protein-1 (UCP1) in skeletal muscle exhibit a healthy aging phenotype with increased longevity and resistance to impaired metabolic health. This may be achieved by decreasing protein glycation by the reactive metabolite, methylglyoxal (MG). We investigated protein glycation and oxidative damage in skeletal muscle of mice with UCP1 expression under control of the human skeletal actin promoter (HSA-mUCP1) at age 12 weeks (young) and 70 weeks (aged). We found both young and aged HSA-mUCP1 mice had decreased advanced glycation endproducts (AGEs) formed from MG, lysine-derived Nε(1-carboxyethyl)lysine (CEL) and arginine-derived hydroimidazolone, MG-H1, whereas protein glycation by glucose forming Nε-fructosyl-lysine (FL) was increased ca. 2-fold, compared to wildtype controls. There were related increases in FL-linked AGEs, Nε-carboxymethyl-lysine (CML) and 3-deoxylglucosone-derived hydroimidazolone 3DG-H, and minor changes in protein oxidative and nitration adducts. In aged HSA-mUCP1 mice, urinary MG-derived AGEs/FL ratio was decreased ca. 60% whereas there was no change in CML/FL ratio - a marker of oxidative damage. This suggests that, normalized for glycemic status, aged HSA-mUCP1 mice had a lower flux of whole body MG-derived AGE exposure compared to wildtype controls. Proteomics analysis of skeletal muscle revealed a shift to increased heat shock proteins and mechanoprotection and repair in HSA-mUCP1 mice. Decreased MG-derived AGE protein content in skeletal muscle of aged HSA-mUCP1 mice is therefore likely produced by increased proteolysis of MG-modified proteins and increased proteostasis surveillance of the skeletal muscle proteome. From this and previous transcriptomic studies, signaling involved in enhanced removal of MG-modified protein is likely increased HSPB1-directed HUWE1 ubiquitination through eIF2α-mediated, ATF5-induced increased expression of HSPB1. Decreased whole body exposure to MG-derived AGEs may be linked to increased weight specific physical activity of HSA-mUCP1 mice. Decreased formation and increased clearance of MG-derived AGEs may be associated with healthy aging in the HSA-mUCP1 mouse.
    Keywords:  Aging; Methylglyoxal; Protein glycation; Proteomics; Skeletal muscle; Uncoupling protein 1
    DOI:  https://doi.org/10.1016/j.redox.2022.102574
  25. Mol Metab. 2022 Dec 09. pii: S2212-8778(22)00221-6. [Epub ahead of print] 101652
    p21 induces a senescence program and skeletal muscle dysfunction.
    Davis A Englund, Alyssa Jolliffe, Zaira Aversa, Xu Zhang, Ines Sturmlechner, Ayumi E Sakamoto, Julianna D Zeidler, Gina M Warner, Colton McNinch, Thomas A White, Eduardo N Chini, Darren J Baker, Jan M van Deursen, Nathan K LeBrasseur.
      Recent work has established associations between elevated p21, the accumulation of senescent cells, and skeletal muscle dysfunction in mice and humans. Using a mouse model of p21 overexpression (p21OE), we examined if p21 mechanistically contributes to cellular senescence and pathological features in skeletal muscle. We show that p21 induces several core properties of cellular senescence in skeletal muscle, including an altered transcriptome, DNA damage, mitochondrial dysfunction, and the senescence-associated secretory phenotype (SASP). Furthermore, p21OE mice exhibit manifestations of skeletal muscle pathology, such as atrophy, fibrosis, and impaired physical function when compared to age-matched controls. These findings suggest p21 alone is sufficient to drive a cellular senescence program and reveal a novel source of skeletal muscle loss and dysfunction.
    Keywords:  Aging; Cellular senescence; DNA damage; Fibrosis; Physical function; Sarcopenia; Senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1016/j.molmet.2022.101652
  26. Dev Growth Differ. 2022 Dec 14.
    Digoxigenin-labeled RNA probes for untranslated regions enable the isoform-specific gene expression analysis of myosin heavy chains in whole-mount in situ hybridization.
    Masafumi Tanji, Keitaro Wada, Keita Sakamoto, Yudai Ono, Masafumi Inui.
      Myosin heavy chains (MyHCs), which are encoded by myosin heavy chain (Myh) genes, are the most abundant proteins in myofiber. Among the 11 sarcomeric Myh isoform genes in the mammalian genome, 7 are mainly expressed in skeletal muscle. Myh genes/MyHC proteins share a common role as force producing units with highly conserved sequences, but have distinct spatio-temporal expression patterns. As such, the expression patterns of Myh genes/MyHC proteins are considered as molecular signatures of specific fiber types or the regenerative status of mammalian skeletal muscles. Immunohistochemistry is widely used for identifying MyHC expression patterns; however, this method is costly and is not ideal for whole-mount samples, such as embryos. In situ hybridization (ISH) is another versatile method for the analysis of gene expression, but is not commonly applied for Myh genes, partly because of the highly homologous sequences of Myh genes. Here we demonstrate that an ISH analysis with the untranslated region (UTR) sequence of Myh genes is cost-effective and specific method for analyzing the Myh gene expression in whole-mount samples. Digoxigenin (DIG)-labeled antisense probes for UTR sequences, but not for protein coding sequences, specifically detected the expression patterns of respective Myh isoform genes in both embryo and adult skeletal muscle tissues. UTR probes also revealed the isoform gene-specific polarized localization of Myh mRNAs in embryonic myofibers, which implied a novel mRNA distribution mechanism. Our data suggested that the DIG-labeled UTR probe is a cost-effective and versatile method to specifically detect skeletal muscle Myh genes in a whole-mount analysis.
    DOI:  https://doi.org/10.1111/dgd.12832
  27. J Cachexia Sarcopenia Muscle. 2022 Dec 14.
    Plasma proteome profiling of healthy subjects undergoing bed rest reveals unloading-dependent changes linked to muscle atrophy.
    Marta Murgia, Lorenza Brocca, Elena Monti, Martino V Franchi, Maximilian Zwiebel, Sophia Steigerwald, Emiliana Giacomello, Roberta Sartori, Sandra Zampieri, Giovanni Capovilla, Mladen Gasparini, Gianni Biolo, Marco Sandri, Matthias Mann, Marco V Narici.
      BACKGROUND: Inactivity and unloading induce skeletal muscle atrophy, loss of strength and detrimental metabolic effects. Bed rest is a model to study the impact of inactivity on the musculoskeletal system. It not only provides information for bed-ridden patients care, but it is also a ground-based spaceflight analogue used to mimic the challenges of long space missions for the human body. In both cases, it would be desirable to develop a panel of biomarkers to monitor muscle atrophy in a minimally invasive way at point of care to limit the onset of muscle loss in a personalized fashion.METHODS: We applied mass spectrometry-based proteomics to measure plasma protein abundance changes in response to 10 days of bed rest in 10 young males. To validate the correlation between muscle atrophy and the significant hits emerging from our study, we analysed in parallel, with the same pipeline, a cohort of cancer patients with or without cachexia and age-matched controls. Our analysis resulted in the quantification of over 500 proteins.
    RESULTS: Unloading affected plasma concentration of proteins of the complement cascade, lipid carriers and proteins derived from tissue leakage. Among the latter, teneurin-4 increased 1.6-fold in plasma at bed rest day 10 (BR10) compared with BR0 (6.E9 vs. 4.3E9, P = 0.02) and decreased to 0.6-fold the initial abundance after 2 days of recovery at normal daily activity (R + 2, 2.7E9, P = 3.3E-4); the extracellular matrix protein lumican was decreased to 0.7-fold (1.2E9 vs. 8.5E8, P = 1.5E-4) at BR10 and remained as low at R + 2. We identified six proteins distinguishing subjects developing unloading-mediated muscle atrophy (decrease of >4% of quadriceps cross-sectional area) from those largely maintaining their initial muscle mass. Among them, transthyretin, a thyroid hormone-binding protein, was significantly less abundant at BR10 in the plasma of subjects with muscle atrophy compared with those with no atrophy (1.6E10 vs. 2.6E10, P = 0.001). Haptoglobin-related protein was also significantly reduced in the serum of cancer patients with cachexia compared with that of controls.
    CONCLUSIONS: Our findings highlight a combination or proteomic changes that can be explored as potential biomarkers of muscle atrophy occurring under different conditions. The panel of significant proteomic differences distinguishing atrophy-prone and atrophy-resistant subjects after 10 days of bed rest need to be tested in a larger cohort to validate their potential to predict inactivity-triggered muscle loss in humans.
    Keywords:  Atrophy; Bed rest; Cachexia; Plasma; Proteomics; Skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.13146
  28. Cells. 2022 Nov 24. pii: 3760. [Epub ahead of print]11(23):
    Alignment of Skeletal Muscle Cells Facilitates Acetylcholine Receptor Clustering and Neuromuscular Junction Formation with Co-Cultured Human iPSC-Derived Motor Neurons.
    Kazunori Shimizu, Haruo Kassai, Yuhei Kamei, Kazuki Yamamoto, Takunori Nagashima, Tadayoshi Maekawa, Hirokazu Akiyama, Hiroyuki Honda.
      In vitro neuromuscular junction (NMJ) models are powerful tools for studying neuromuscular disorders. Although linearly patterned culture surfaces have been reported to be useful for the formation of in vitro NMJ models using mouse motor neuron (MNs) and skeletal muscle (SkM) myotubes, it is unclear how the linearly patterned culture surface increases acetylcholine receptor (AChR) clustering, one of the steps in the process of NMJ formation, and whether this increases the in vitro NMJ formation efficiency of co-cultured human MNs and SkM myotubes. In this study, we investigated the effects of a linearly patterned culture surface on AChR clustering in myotubes and examined the possible mechanism of the increase in AChR clustering using gene expression analysis, as well as the effects of the patterned surface on the efficiency of NMJ formation between co-cultured human SkM myotubes and human iPSC-derived MNs. Our results suggest that better differentiation of myotubes on the patterned surface, compared to the flat surface, induced gene expression of integrin α7 and AChR ε-subunit, thereby increasing AChR clustering. Furthermore, we found that the number of NMJs between human SkM cells and MNs increased upon co-culture on the linearly patterned surface, suggesting the usefulness of the patterned surface for creating in vitro human NMJ models.
    Keywords:  co-culture; micropatterns; motor neuron; skeletal muscle
    DOI:  https://doi.org/10.3390/cells11233760
  29. Int J Mol Sci. 2022 Nov 30. pii: 14989. [Epub ahead of print]23(23):
    Golgi Complex form and Function: A Potential Hub Role Also in Skeletal Muscle Pathologies?
    Luana Toniolo, Giuseppe Sirago, Nicola Fiotti, Emiliana Giacomello.
      A growing number of disorders has been associated with mutations in the components of the vesicular transport machinery. The early secretory pathway consists of Endoplasmic Reticulum, numerous vesicles, and the Golgi Complex (GC), which work together to modify and package proteins to deliver them to their destination. The GC is a hub organelle, crucial for organization of the other secretory pathway components. As a consequence, GC's form and function are key players in the pathogenesis of several disorders. Skeletal muscle (SKM) damage can be caused by defective protein modifications and traffic, as observed in some Limb girdle muscular dystrophies. Interestingly, in turn, muscle damage in Duchenne dystrophic SKM cells also includes the alteration of GC morphology. Based on the correlation between GC's form and function described in non-muscle diseases, we suggest a key role for this hub organelle also in the onset and progression of some SKM disorders. An altered GC could affect the secretory pathway via primary (e.g., mutation of a glycosylation enzyme), or secondary mechanisms (e.g., GC mis-localization in Duchenne muscles), which converge in SKM cell failure. This evidence induces considering the secretory pathway as a potential therapeutic target in the treatment of muscular dystrophies.
    Keywords:  Golgi Complex; Limb girdle muscular dystrophy; dystrophin associated protein complex; early secretory pathway; glycosylation; muscular dystrophy
    DOI:  https://doi.org/10.3390/ijms232314989
  30. Exp Neurol. 2022 Dec 13. pii: S0014-4886(22)00325-9. [Epub ahead of print] 114300
    Proteolytic ectodomain shedding of muscle-specific tyrosine kinase in myasthenia gravis.
    Shuuichi Mori, Shigeaki Suzuki, Tetsuro Konishi, Naoki Kawaguchi, Masahiko Kishi, Satoshi Kuwabara, Kei Ishizuchi, Heying Zhou, Futoshi Shibasaki, Hiroki Tsumoto, Takuya Omura, Yuri Miura, Seijiro Mori, Mana Higashihara, Shigeo Murayama, Kazuhiro Shigemoto.
      Autoantibodies to muscle-specific tyrosine kinase (MuSK) proteins at the neuromuscular junction (NMJ) cause refractory generalized myasthenia gravis (MG) with dyspnea more frequently than other MG subtypes. However, the mechanisms via which MuSK, a membrane protein locally expressed on the NMJ of skeletal muscle, is supplied to the immune system as an autoantigen remains unknown. Here, we identified MuSK in both mouse and human serum, with the amount of MuSK dramatically increasing in mice with motor nerve denervation and in MG model mice. Peptide analysis by liquid chromatography-tandem-mass spectrometry (LC-MS/MS) confirmed the presence of MuSK in both human and mouse serum. Furthermore, some patients with MG have significantly higher amounts of MuSK in serum than healthy controls. Our results indicated that the secretion of MuSK proteins from muscles into the bloodstream was induced by ectodomain shedding triggered by neuromuscular junction failure. The results may explain why MuSK-MG is refractory to treatments and causes rapid muscle atrophy in some patients due to the denervation associated with Ab-induced disruption of neuromuscular transmission at the NMJ. Such discoveries pave the way for new MG treatments, and MuSK may be used as a biomarker for other neuromuscular diseases in preclinical studies, clinical diagnostics, therapeutics, and drug discovery.
    Keywords:  Animal model; Biomarker; Denervation; Extracellular domain; Mass spectrometry; Matrix protease; Muscle-specific kinase; Myasthenia gravis; Reinnervation; Shedding
    DOI:  https://doi.org/10.1016/j.expneurol.2022.114300
  31. bioRxiv. 2022 Nov 09. pii: 2020.12.20.423533. [Epub ahead of print]
    Infection and chronic disease activate a brain-muscle signaling axis that regulates muscle performance.
    Shuo Yang, Meijie Tian, Yulong Dai, Shengyong Feng, Yunyun Wang, Deepak Chhangani, Tiffany Ou, Wenle Li, Ze Yang, Jennifer McAdow, Diego E Rincon-Limas, Xin Yin, Wanbo Tai, Gong Cheng, Aaron Johnson.
      Graphic abstract: Summary: Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show a number of non-neural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood, so we developed three models to investigate the impact of neuroinflammation on muscle performance. We found that bacterial infection, COVID-like viral infection, and expression of a neurotoxic protein associated with Alzheimer′ s disease promoted the accumulation of reactive oxygen species (ROS) in the brain. Excessive ROS induces the expression of the cytokine Unpaired 3 (Upd3) in insects, or its orthologue IL-6 in mammals, and CNS-derived Upd3/IL-6 activates the JAK/Stat pathway in skeletal muscle. In response to JAK/Stat signaling, mitochondrial function is impaired and muscle performance is reduced. Our work uncovers a brain-muscle signaling axis in which infections and chronic diseases induce cytokine-dependent changes in muscle performance, suggesting IL-6 could be a therapeutic target to treat muscle weakness caused by neuroinflammation.
    DOI:  https://doi.org/10.1101/2020.12.20.423533
  32. Exp Gerontol. 2022 Dec 12. pii: S0531-5565(22)00355-2. [Epub ahead of print] 112046
    Muscle PGC-1α modulates hepatic mitophagy regulation during aging.
    Natascha Masselkhi Christensen, Stine Ringholm, Bjørg Thiellesen Buch, Anders Gudiksen, Jens Frey Halling, Henriette Pilegaard.
      Aging has been suggested to be associated with changes in oxidative capacity, autophagy, and mitophagy in the liver, but a simultaneous evaluation of these key cellular processes is lacking. Moreover, skeletal muscle Transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator(PGC)-1α has been reported to mediate inter-organ signaling through myokines with regulatory effects in the liver, but the potential role of muscle PGC-1α on hepatic changes with age remains to be resolved. The aim of the present study was therefore to investigate 1) the effect of aging on mitochondrial autophagy and mitophagy capacity in mouse liver and 2) whether muscle PGC-1α is required for maintaining autophagy and mitophagy capacity in the liver during aging. The liver was obtained from young (Young) and aged (Aged) inducible muscle-specific PGC-1α knockout (iMKO) and floxed littermate control mice. Aging increased liver p62, Parkin and Protein-interacting protein(BNIP)3 protein with no effect of muscle specific PGC-1α knockout, while liver Microtubule-associated protein 1A/1B-light chain 3(LC3) II/I was unchanged with age, but tended to be lower in iMKO mice than in controls. Markers of liver mitochondrial oxidative capacity and oxidative stress were unchanged with age and iMKO. However, Parkin protein levels in isolated liver mitochondria were 2-fold higher in Aged iMKO mice than in Aged controls. In conclusion, aging had no effect on oxidative capacity and redox stress in the liver. However, aging was associated with increased levels of autophagy and mitophagy markers. Moreover, muscle PGC-1α appears to regulate hepatic mitochondrial translocation of Parkin in aged mice, suggesting that the metabolic capacity of skeletal muscle can modulate mitophagy regulation of the liver during aging.
    Keywords:  Aging; Autophagy; Liver; Metabolism; PGC-1a; Parkin
    DOI:  https://doi.org/10.1016/j.exger.2022.112046
  33. J Cachexia Sarcopenia Muscle. 2022 Dec 13.
    AMP-activated protein kinase inhibition in fibro-adipogenic progenitors impairs muscle regeneration and increases fibrosis.
    Xiangdong Liu, Liang Zhao, Yao Gao, Yanting Chen, Qiyu Tian, Jun Seok Son, Song Ah Chae, Jeanene Marie de Avila, Mei-Jun Zhu, Min Du.
      BACKGROUND: Following muscle injury, fibro-adipogenic progenitors (FAPs) are rapidly activated and undergo apoptosis at the resolution stage, which is required for proper muscle regeneration. When excessive FAPs remain, it contributes to fibrotic and fatty infiltration, impairing muscle recovery. Mechanisms controlling FAP apoptosis remain poorly defined. We hypothesized that AMP-activated protein kinase (AMPK) in FAPs mediates their apoptosis during the muscle regeneration.METHODS: To test, AMPKα1fl/fl PDGFRαCre mice were used to knock out AMPKα1 in FAPs. Following AMPKα1 knockout, the mice were injected with phosphate-buffered saline or glycerol to induce muscle injury. Tibialis anterior muscle and FAPs were collected at 3, 7 and 14 days post-injury (dpi) for further analysis.
    RESULTS: We found that AMPKα1 deletion in FAPs enhanced p65 translocation to the nuclei by 110% (n = 3; P < 0.01). AMPKα1 knockout group had a higher gene expression of MMP-9 (matrix metalloproteinase-9) by 470% (n = 3; P < 0.05) and protein level by 39% (n = 3; P < 0.05). Loss of AMPKα1 up-regulated the active TGF-β1 (transforming growth factor-β1) levels by 21% (n = 3; P < 0.05). TGF-β promoted apoptotic resistance, because AMPKα1-deficient group had 36% lower cleaved Caspase 3 (cCAS3) content (n = 3; P < 0.05). Fibrotic differentiation of FAPs was promoted, with increased collagen protein level by 54% (n = 3; P < 0.05). Moreover, obesity decreased phosphorylation of AMPK by 54% (n = 3; P < 0.05), which decreased cCAS3 in FAPs by 44% (n = 3; P < 0.05) and elevated collagen accumulation (52%; n = 3; P < 0.05) during muscle regeneration.
    CONCLUSIONS: These data suggest that AMPK is a key mediator of FAPs apoptosis, and its inhibition due to obesity results in fibrosis of regenerated muscle.
    Keywords:  AMPK; FAPs; MMP-9; TGF-β; fibrosis; obesity
    DOI:  https://doi.org/10.1002/jcsm.13150
  34. Acta Neuropathol. 2022 Dec 13.
    Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4.
    Michio Inoue, Satoru Noguchi, Yukiko U Inoue, Aritoshi Iida, Megumu Ogawa, Rocio Bengoechea, Sara K Pittman, Shinichiro Hayashi, Kazuki Watanabe, Yasushi Hosoi, Terunori Sano, Masaki Takao, Yasushi Oya, Yuji Takahashi, Hiroaki Miyajima, Conrad C Weihl, Takayoshi Inoue, Ichizo Nishino.
      DnaJ homolog, subfamily B, member 4, a member of the heat shock protein 40 chaperones encoded by DNAJB4, is highly expressed in myofibers. We identified a heterozygous c.270 T > A (p.F90L) variant in DNAJB4 in a family with a dominantly inherited distal myopathy, in which affected members have specific features on muscle pathology represented by the presence of cytoplasmic inclusions and the accumulation of desmin, p62, HSP70, and DNAJB4 predominantly in type 1 fibers. Both Dnajb4F90L knockin and knockout mice developed muscle weakness and recapitulated the patient muscle pathology in the soleus muscle, where DNAJB4 has the highest expression. These data indicate that the identified variant is causative, resulting in defective chaperone function and selective muscle degeneration in specific muscle fibers. This study demonstrates the importance of DNAJB4 in skeletal muscle proteostasis by identifying the associated chaperonopathy.
    DOI:  https://doi.org/10.1007/s00401-022-02530-4
  35. Int J Mol Sci. 2022 Nov 24. pii: 14657. [Epub ahead of print]23(23):
    Immunoproteasome Inhibition Ameliorates Aged Dystrophic Mouse Muscle Environment.
    Luana Tripodi, Davide Molinaro, Francesco Fortunato, Carolina Mella, Barbara Cassani, Yvan Torrente, Andrea Farini.
      Muscle wasting is a major pathological feature observed in Duchenne muscular dystrophy (DMD) and is the result of the concerted effects of inflammation, oxidative stress and cell senescence. The inducible form of proteasome, or immunoproteasome (IP), is involved in all the above mentioned processes, regulating antigen presentation, cytokine production and immune cell response. IP inhibition has been previously shown to dampen the altered molecular, histological and functional features of 3-month-old mdx mice, the animal model for DMD. In this study, we described the role of ONX-0914, a selective inhibitor of the PSMB8 subunit of immunoproteasome, in ameliorating the pathological traits that could promote muscle wasting progression in older, 9-month-old mdx mice. ONX-0914 reduces the number of macrophages and effector memory T cells in muscle and spleen, while increasing the number of regulatory T cells. It modulates inflammatory markers both in skeletal and cardiac muscle, possibly counteracting heart remodeling and hypertrophy. Moreover, it buffers oxidative stress by improving mitochondrial efficiency. These changes ultimately lead to a marked decrease of fibrosis and, potentially, to more controlled myofiber degeneration/regeneration cycles. Therefore, ONX-0914 is a promising molecule that may slow down muscle mass loss, with relatively low side effects, in dystrophic patients with moderate to advanced disease.
    Keywords:  aging; immunoproteasome; inflammation; muscle mass; sarcopenia
    DOI:  https://doi.org/10.3390/ijms232314657
  36. Cell Biochem Funct. 2022 Dec 14.
    Aging reduces ABHD5 protein content in the adipose tissue of mice: The reversal effect of exercise.
    Rafael S Brícola, André V Cordeiro, Barbara M Crisol, Renata R Braga, Diego G de Melo, Matheus B Rocha, Rafael C Gaspar, Susana C B R Nakandakari, Vagner R R Silva, Chadi P Anaruma, Carlos K Katashima, Raphael D S Canciglieri, Vitor R Munõz, Isadora C B Pavan, Ana P Pinto, Fernando M Simabuco, Adelino S R da Silva, Leandro P Moura, José R Pauli, Dennys E Cintra, Eduardo R Ropelle.
      Dysfunction of the adipose tissue metabolism is considered as a significant hallmark of aging. It has been proposed that α-β hydrolase domain containing 5 (ABHD5) plays a critical role in the control of lipolysis. However, the role of ABHD5 in the control of lipolysis during aging or exercise is unknown. Here we combined the experimental mouse model with transcriptomic analyzes by using murine and human databases to explore the role of ABHD5 in the adipose tissue during aging and in response to exercise. Transcriptomic data revealed a downregulation of Abhd5 messenger RNA levels in the subcutaneous white adipose tissue (scWAT) over time in individuals from 20 to 69 years old. Aged mice displayed dramatic reduction of ABHD5 protein content and lipolytic-related proteins in the scWAT. Interestingly, 4 weeks of high-intensity interval training increased ABHD5 protein level and restored the lipolytic pathway in the scWAT of aged mice. Altogether, our findings demonstrated that aging affects ABHD5 content in the adipose tissue of mice and humans. Conversely, exercise increases ABHD5 activity, recovering the lipolytic activity in aged mice.
    Keywords:  ABHD5; adipose tissue; aging; physical exercise and lipolysis
    DOI:  https://doi.org/10.1002/cbf.3770
  37. Mech Ageing Dev. 2022 Dec 09. pii: S0047-6374(22)00144-0. [Epub ahead of print] 111762
    Age, sex, and frailty modify the expression of common reference genes in skeletal muscle from ageing mice.
    Manish Mishra, Alice E Kane, Alexander P Young, Susan E Howlett.
      Changes in gene expression with age are typically normalised to constitutively expressed reference genes (RGs). However, RG expression may be affected by age or overall health and most studies use only male animals. We investigated whether expression of common RGs (Gapdh, Gusb, Rplp0, B2m, Tubb5, Rpl7l1, Hprt, Rer1) was affected by age, sex and/or overall health (frailty index) in skeletal muscle from young (4-mos) and aged (25-26-mos) mice. Standard RG selection programs recommended Gapdh (RefFinder/Genorm/NormFinder) or Rpl7l1 (BestKeeper) without considering age and sex. Analysis of raw Cq values showed only Rplp0 was stable in both sexes at both ages. When qPCR data were normalised to Rplp0, age affected RG expression, especially in females. For example, Hprt expression declined with age (Hprt=9.8×10-2±4.7×10-2 vs. 6.5×10-3±8.8×10-4; mean±SEM), while Gusb expression increased (6.0×10-4±5.5×10-5 vs. 1.7×10-3±3.1×10-4; n=5/group; p<0.05). These effects were not seen in males. Tubb5 and Gapdh were not affected by age or sex when normalised to Rplp0. Similar results were seen with normalisation by Gapdh or the Rplp0/Gapdh pair. Interestingly, RG expression was graded not only by age but by frailty. These data demonstrate that age, sex, and frailty of animals must be carefully considered when selecting RGs to normalise mRNA abundance data.
    Keywords:  -; Reference gene; ageing; frailty index; healthspan; sarcopenia; sex differences
    DOI:  https://doi.org/10.1016/j.mad.2022.111762
  38. Int J Mol Sci. 2022 Nov 30. pii: 15039. [Epub ahead of print]23(23):
    Inflammaging: Implications in Sarcopenia.
    Eduardo Antuña, Cristina Cachán-Vega, Juan Carlos Bermejo-Millo, Yaiza Potes, Beatriz Caballero, Ignacio Vega-Naredo, Ana Coto-Montes, Claudia Garcia-Gonzalez.
      In a world in which life expectancy is increasing, understanding and promoting healthy aging becomes a contemporary demand. In the elderly, a sterile, chronic and low-grade systemic inflammation known as "inflammaging" is linked with many age-associated diseases. Considering sarcopenia as a loss of strength and mass of skeletal muscle related to aging, correlations between these two terms have been proposed. Better knowledge of the immune system players in skeletal muscle would help to elucidate their implications in sarcopenia. Characterizing the activators of damage sensors and the downstream effectors explains the inference with skeletal muscle performance. Sarcopenia has also been linked to chronic diseases such as diabetes, metabolic syndrome and obesity. Implications of inflammatory signals from these diseases negatively affect skeletal muscle. Autophagic mechanisms are closely related with the inflammasome, as autophagy eliminates stress signaling sent by damage organelles, but also acts with an immunomodulatory function affecting immune cells and cytokine release. The use of melatonin, an antioxidant, ROS scavenger and immune and autophagy modulator, or senotherapeutic compounds targeting senescent cells could represent strategies to counteract inflammation. This review aims to present the many factors regulating skeletal muscle inflammaging and their major implications in order to understand the molecular mechanisms involved in sarcopenia.
    Keywords:  aging; inflammation; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms232315039
  39. J Appl Physiol (1985). 2022 Dec 15.
    Exercise and mitochondrial remodeling to prevent age-related neurodegeneration.
    Colleen L O'Reilly, Benjamin F Miller, Tommy L Lewis.
      Healthy brain activity requires precise ion and energy management creating a strong reliance on mitochondrial function. Age-related neurodegeneration leads to a decline in mitochondrial function and increased oxidative stress, with associated declines in mitochondrial mass, respiration capacity, and respiration efficiency. The interdependent processes of mitochondrial protein turnover and mitochondrial dynamics, known together as mitochondrial remodeling, play essential roles in mitochondrial health and therefore brain function. This mini-review describes the role of mitochondria in neurodegeneration and brain health, current practices for assessing both aspects of mitochondrial remodeling, and how exercise mitigates the adverse effects of aging in the brain. Exercise training elicits functional adaptations to improve brain health, and current literature strongly suggests that mitochondrial remodeling plays a vital role in these positive adaptations. Despite substantial implications that the two aspects of mitochondrial remodeling are interdependent, very few investigations have simultaneously measured mitochondrial dynamics and protein synthesis. An improved understanding of the partnership between mitochondrial protein turnover and mitochondrial dynamics will provide a better understanding of their role in both brain health and disease, as well as how they induce protection following exercise.
    Keywords:  brain; exercise; mitochondria; mitochondria remodeling; neurodegeneration
    DOI:  https://doi.org/10.1152/japplphysiol.00611.2022
  40. Sci Rep. 2022 Dec 14. 12(1): 21576
    CRISPR-mediated generation and characterization of a Gaa homozygous c.1935C>A (p.D645E) Pompe disease knock-in mouse model recapitulating human infantile onset-Pompe disease.
    Shih-Hsin Kan, Jeffrey Y Huang, Jerry Harb, Allisandra Rha, Nancy D Dalton, Chloe Christensen, Yunghang Chan, Jeremy Davis-Turak, Jonathan Neumann, Raymond Y Wang.
      Pompe disease, an autosomal recessive disorder caused by deficient lysosomal acid α-glucosidase (GAA), is characterized by accumulation of intra-lysosomal glycogen in skeletal and oftentimes cardiac muscle. The c.1935C>A (p.Asp645Glu) variant, the most frequent GAA pathogenic mutation in people of Southern Han Chinese ancestry, causes infantile-onset Pompe disease (IOPD), presenting neonatally with severe hypertrophic cardiomyopathy, profound muscle hypotonia, respiratory failure, and infantile mortality. We applied CRISPR-Cas9 homology-directed repair (HDR) using a novel dual sgRNA approach flanking the target site to generate a Gaaem1935C>A knock-in mouse model and a myoblast cell line carrying the Gaa c.1935C>A mutation. Herein we describe the molecular, biochemical, histological, physiological, and behavioral characterization of 3-month-old homozygous Gaaem1935C>A mice. Homozygous Gaaem1935C>A knock-in mice exhibited normal Gaa mRNA expression levels relative to wild-type mice, had near-abolished GAA enzymatic activity, markedly increased tissue glycogen storage, and concomitantly impaired autophagy. Three-month-old mice demonstrated skeletal muscle weakness and hypertrophic cardiomyopathy but no premature mortality. The Gaaem1935C>A knock-in mouse model recapitulates multiple salient aspects of human IOPD caused by the GAA c.1935C>A pathogenic variant. It is an ideal model to assess innovative therapies to treat IOPD, including personalized therapeutic strategies that correct pathogenic variants, restore GAA activity and produce functional phenotypes.
    DOI:  https://doi.org/10.1038/s41598-022-25914-8
  41. Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01674-6. [Epub ahead of print]41(11): 111786
    Divergent remodeling of the skeletal muscle metabolome over 24 h between young, healthy men and older, metabolically compromised men.
    Jan-Frieder Harmsen, Michel van Weeghel, Rex Parsons, Georges E Janssens, Jakob Wefers, Dirk van Moorsel, Jan Hansen, Joris Hoeks, Matthijs K C Hesselink, Riekelt H Houtkooper, Patrick Schrauwen.
      24 h whole-body substrate metabolism and the circadian clock within skeletal muscle are both compromised upon metabolic disease in humans. Here, we assessed the 24 h muscle metabolome by serial muscle sampling performed under 24 h real-life conditions in young, healthy (YH) men versus older, metabolically compromised (OMC) men. We find that metabolites associated with the initial steps of glycolysis and hexosamine biosynthesis are higher in OMC men around the clock, whereas metabolites associated with glutamine-alpha-ketoglutarate, ketone, and redox metabolism are lower in OMC men. The night period shows the largest number of differently expressed metabolites. Both groups demonstrate 24 h rhythmicity in half of the metabolome, but rhythmic metabolites only partially overlap. Specific metabolites are only rhythmic in YH men (adenosine), phase shifted in OMC men (cis-aconitate, flavin adenine dinucleotide [FAD], and uridine diphosphate [UDP]), or have a reduced 24 h amplitude in OMC men (hydroxybutyrate and hippuric acid). Our data highlight the plasticity of the skeletal muscle metabolome over 24 h and large divergence across the metabolic health spectrum.
    Keywords:  CP: Metabolism; FAD; PGK1; adenosine; circadian rhythm; glycolysis; hexosamine; hydroxybutyrate; insulin resistance; metabolomics; misalignment
    DOI:  https://doi.org/10.1016/j.celrep.2022.111786
  42. Expert Opin Ther Targets. 2022 Dec 16.
    Early clinical and pre-clinical therapy development in Nemaline Myopathy.
    Gemma Fisher, Laurane Mackels, Theodora Markati, Anna Sarkozy, Julien Ochala, Heinz Jungbluth, Sithara Ramdas, Laurent Servais.
      INTRODUCTION: : Nemaline myopathies (NM) represent a group of clinically and genetically heterogeneous congenital muscle disorders with the common denominator of nemaline rods on muscle biopsy. NEB and ACTA1 are the most common causative genes. Currently available treatments are supportive.AREAS COVERED: We explored experimental treatments for NM, identifying at least eleven mainly pre-clinical approaches utilizing murine and/or human muscle cells. These approaches target either i) the causative gene or associated genes implicated in the same pathway; ii) pathophysiologically relevant biochemical mechanisms such as calcium/myosin regulation of muscle contraction; iii) myogenesis; iv) other therapies that improve or optimise muscle function more generally; v) and/or combinations of the above. The scope and efficiency of these attempts is diverse, ranging from gene-specific effects to those widely applicable to all NM-associated genes.
    EXPERT OPINION: : The wide range of experimental therapies currently under consideration for NM is promising. Potential translation into clinical use requires consideration of additional factors such as the potential muscle type specificity as well as the possibility of gene expression remodelling. Challenges to clinical translation include the rarity and heterogeneity of genotypes, phenotypes and disease trajectories, as well as lack of longitudinal natural history data and validated outcomes and biomarkers.
    Keywords:  ACTA1; NEB; congenital myopathy; exon skipping; fast troponin activators; gene therapy; myostatin; pyridostigmine
    DOI:  https://doi.org/10.1080/14728222.2022.2157258
  43. Nat Commun. 2022 Dec 17. 13(1): 7792
    Muscle 4EBP1 activation modifies the structure and function of the neuromuscular junction in mice.
    Seok-Ting J Ang, Elisa M Crombie, Han Dong, Kuan-Ting Tan, Adriel Hernando, Dejie Yu, Stuart Adamson, Seonyoung Kim, Dominic J Withers, Hua Huang, Shih-Yin Tsai.
      Dysregulation of mTOR complex 1 (mTORC1) activity drives neuromuscular junction (NMJ) structural instability during aging; however, downstream targets mediating this effect have not been elucidated. Here, we investigate the roles of two mTORC1 phosphorylation targets for mRNA translation, ribosome protein S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), in regulating NMJ structural instability induced by aging and sustained mTORC1 activation. While myofiber-specific deletion of S6k1 has no effect on NMJ structural integrity, 4EBP1 activation in murine muscle induces drastic morphological remodeling of the NMJ with enhancement of synaptic transmission. Mechanistically, structural modification of the NMJ is attributed to increased satellite cell activation and enhanced post-synaptic acetylcholine receptor (AChR) turnover upon 4EBP1 activation. Considering that loss of post-synaptic myonuclei and reduced NMJ turnover are features of aging, targeting 4EBP1 activation could induce NMJ renewal by expanding the pool of post-synaptic myonuclei as an alternative intervention to mitigate sarcopenia.
    DOI:  https://doi.org/10.1038/s41467-022-35547-0
  44. Cells. 2022 Dec 02. pii: 3910. [Epub ahead of print]11(23):
    Genome-Wide Association Study Identifies CDKN1A as a Novel Locus Associated with Muscle Fiber Composition.
    Ekaterina A Semenova, Hirofumi Zempo, Eri Miyamoto-Mikami, Hiroshi Kumagai, Andrey K Larin, Rinat I Sultanov, Konstantin A Babalyan, Andrey V Zhelankin, Takuro Tobina, Keisuke Shiose, Ryo Kakigi, Takamasa Tsuzuki, Noriko Ichinoseki-Sekine, Hiroyuki Kobayashi, Hisashi Naito, Jatin Burniston, Edward V Generozov, Noriyuki Fuku, Ildus I Ahmetov.
      Muscle fiber composition is associated with physical performance, with endurance athletes having a high proportion of slow-twitch muscle fibers compared to power athletes. Approximately 45% of muscle fiber composition is heritable, however, single nucleotide polymorphisms (SNP) underlying inter-individual differences in muscle fiber types remain largely unknown. Based on three whole genome SNP datasets, we have shown that the rs236448 A allele located near the cyclin-dependent kinase inhibitor 1A (CDKN1A) gene was associated with an increased proportion of slow-twitch muscle fibers in Russian (n = 151; p = 0.039), Finnish (n = 287; p = 0.03), and Japanese (n = 207; p = 0.008) cohorts (meta-analysis: p = 7.9 × 10-5. Furthermore, the frequency of the rs236448 A allele was significantly higher in Russian (p = 0.045) and Japanese (p = 0.038) elite endurance athletes compared to ethnically matched power athletes. On the contrary, the C allele was associated with a greater proportion of fast-twitch muscle fibers and a predisposition to power sports. CDKN1A participates in cell cycle regulation and is suppressed by the miR-208b, which has a prominent role in the activation of the slow myofiber gene program. Bioinformatic analysis revealed that the rs236448 C allele was associated with increased CDKN1A expression in whole blood (p = 8.5 × 10-15) and with greater appendicular lean mass (p = 1.2 × 10-5), whereas the A allele was associated with longer durations of exercise (p = 0.044) reported amongst the UK Biobank cohort. Furthermore, the expression of CDKN1A increased in response to strength (p &lt; 0.0001) or sprint (p = 0.00035) training. Accordingly, we found that CDKN1A expression is significantly (p = 0.002) higher in the m. vastus lateralis of strength athletes compared to endurance athletes and is positively correlated with the percentage of fast-twitch muscle fibers (p = 0.018). In conclusion, our data suggest that the CDKN1A rs236448 SNP may be implicated in the determination of muscle fiber composition and may affect athletic performance.
    Keywords:  DNA; GWAS; athletic performance; endurance; exercise; genetic markers; genotype; muscle fibers; sports; sprinters; talent identification
    DOI:  https://doi.org/10.3390/cells11233910
  45. Eur J Transl Myol. 2022 Dec 13.
    2023 On-site Padua Days on Muscle and Mobiliy Medicine: Call for speakers.
    Sandra Zampieri, Carla Stecco, Marco Narici, Stefano Masiero, Ugo Carraro.
      The winter of 2022 approaches with the need to finalize our plans for next year. This is urgent for the 2023 Meeting of the Padua Days of Muscle and Mobility Medicine (Pdm3) to be held March 29th to April 1st, 2023 at the Hotel Petrarca in the Thermae of Euganean Hills (Padua), Italy. A preliminary Pdm3 Program is almost ready with sessions, organzers and keynote speakers, but ther is still rooms for many interesting and interested young speakers. Some of the Pdm3 sessions dedicated to molecular and cellular myology are organized by old Pdm3 Friends, but there will also be interesting new entries, including those for Rehabilitation Sessions. No doubt that 2023 Pdm3 will attract old friends, but topics of a few sessions are at the frontiers of Translational Myology and new entries are most warmly acknowledged. This is true for both basic myology research, which include beside traditional MiRNA the new entry of the LNC-RNA and the "dark side of the genome". As to rehabilitation topics, beside the old friends of the "LBI workshop on muscle rehabilitation - from mouse to elderly", new entries are sessions on Muscle Fascia, Muscle Rehabilitation in Dentistry (that will organize also a Practical Course) and the session on "European Medical Thermalism and FEMTEC" that will also offer a practical Course. We hope that by January 20th, 2023 many old and new friends will send their abstracts to fill an half-empty program and then by May 1st, 2023 they submit Communications to EJTM that deserve them to increase the 2023 EJTM Impact Factor.
    DOI:  https://doi.org/10.4081/ejtm.2022.11071
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